Project Summary: The objective of this exploratory/developmental R21 application is to characterize and better understand the effects of genetic polymorphisms in the dopamine system on stress- & smoking cue- induced cigarette cravings and smoking cessation among women who smoke. Grounded in a diverse literature, the proposed multidisciplinary prospective study of women interested in making an untreated, 'cold turkey' smoking cessation attempt will provide a naturalistic look at potential effects of dopamine-related genotypes and stress- & cue-induced cravings elicited under laboratory conditions, on abstinence. To that end, 250 women will be genotyped for dopamine-related polymorphisms, participate in laboratory stress and cue-exposure tasks the day before their target quit date, and will be assessed for abstinence at 8 time points during a 6-month follow-up interval. By closely examining relations between experimentally-induced craving reactions and cessation, the study will attempt to better characterize mechanisms underlying the effects of dopamine genotypes. This first study will lay the groundwork for larger-scale investigations aimed at determining the beneficial effects of tailored treatments (e.g., cue-exposure, stress management, nicotine replacement) in the context of genetic (e.g., dopamine polymorphisms) and psychobiological (e.g., cue- and stress-induced craving reactions) characteristics in samples of both men and women, with an eye toward yielding a better undestanding of the unique challenges experienced by women trying to quit smoking. Relevance: Smoking is the single most preventable cause of morbidity and mortality in the United States. Indeed, smoking has been implicated in at least 30 percent of all cancer deaths in the U.S. and an estimated three million deaths per year worldwide. In spite of the clear negative consequences of smoking, a significant subset of the population continues to smoke. Moreover, although most smokers express a strong interest in quitting, few are successful at maintaining abstinence, a problem that is even more pronounced among women. Persistent smoking behavior (i.e., failure or difficulty in remaining abstinent) thus continues to be a major public health problem. Understanding the genetic and psychobiological determinants of smoking cessation success is a critical first step in developing novel approaches to promote cessation, so necessary to reduce the alarming rates of cancer and other smoking-related chronic diseases. [unreadable] [unreadable] [unreadable] [unreadable]